Leading with quality: Variant classification

June 5, 2017

What does it mean to be at the forefront of genetic testing? At Invitae, we believe it includes both high quality testing and a dedication to improving medicine through data sharing.

We recently published our approach to variant classification in Genetics in Medicine, the official journal of the American College of Medical Genetics and Genomics (ACMG). The paper describes our variant classification process, which represents a significant improvement in clinical genetic testing.

Background

Variant classification guidelines issued by ACMG and the Association for Molecular Pathology (AMP) were a major step toward establishing a common framework for variant classification. In practice, however, it is recognized by ClinGen and other groups that several aspects of the guidelines lack specificity, are subject to varied interpretations, or fail to capture relevant aspects of clinical molecular genetics. A simple implementation of the guidelines in their current form is insufficient for consistent and comprehensive variant classification, and additional refinements are necessary to ensure that variant classifications are systematic, accurate, and reproducible.

Invitae’s high-quality, fully transparent method

Our clinical genomics group used the ACMG–AMP guidelines to classify more than 40,000 clinically observed variants, and refined the classification criteria to capture exceptions and edge cases.

The result is a set of discrete, numerically weighted rules that enable a thoroughly consistent and transparent approach to variant classification. It is built on the strong framework of the 33 rules established by the ACMG–AMP guidelines, augmented by 108 detailed refinements. For any areas where the guidelines resulted in clinical ambiguity, we added rules to ensure accurate and reproducible classification. This variant classification system—which Invitae uses for all tests—enables objective and reproducible results, a cornerstone of clinically valid and scientifically accurate genetic testing.

Why is this important?

Our method of variant classification enables comprehensive review of the available literature and evidence, clear logic and conclusions, and clear explanations. We believe our approach results in better treatment and care. In addition, by publishing our method in the public domain, without copyright or intellectual property claims, we encourage other laboratories to also use reproducible, transparent methods in their variant classification. The Genetics in Medicine paper describes our method in great detail, allowing other laboratories to apply the system if desired. Although many, but not all, clinical testing laboratories submit their variant classifications into ClinVar, Invitae is among a small handful of clinical laboratories that submit not only all variant classifications but also the evidence and rationale that support each of our classifications. By sharing information, through both papers like this one and ClinVar submissions that detail evidence, Invitae enables the discussion of evidence and weighting, thereby improving variant classification and the resulting medical care.

Test your testing providers

We encourage you to test all your testing providers by asking:

Has the lab’s variant classification methodology been peer reviewed?

Does the lab’s variant classification method have bias?

Will two different geneticists at the lab classify a variant the same, or is classification subject to personal interpretation?

If you have any questions about Invitae’s approach to variant classification—or about our overall dedication to high-quality testing—please don’t hesitate to contact Client Services. We look forward to hearing from you.